The multitude of mechanisms that lead to general break of tolerance and organ pathology in patients with systemic lupus erythematosus (SLE) have challenged both basic immunologists and translational researchers. Infections remain one of the main causes of morbidity and mortality among patients with SLE despite our significantly improved ability to diagnose and treat infections early and efficiently. Search for genes expressed in T cells from patients with SLE revealed CD38 to be associated with more severe disease and extensive aberrant gene expression. CD8+CD38+ T cells were found expanded in patients with SLE and to be strongly associated with increased infection rates. CD8+CD38+ cells display compromised cytotoxic activity, less amounts of nicotinamide adenine dinucleotide (NAD+), decreased glycolysis and oxidative phosphorylation and decreased expression of molecules responsible for the performance of cytotoxic cell function. In addition, inhibition of CD38 appeared to restore aspects of cytotoxic cell function. The hypothesis which will guide the proposed studies is: increased expression of CD38 on CD8+ cells in patients with SLE and lupus-prone mice compromises their cytotoxic activity and predisposes to infections and drives autoimmunity. Three sets of experiments using human cells and novel mice will be conducted to test the hypothesis. The first will determine how CD38 expression limits cytotoxicity in CD8 cells. The second will explore approaches to enhance cytotoxic responses of SLE CD8+ cells including targeted delivery of drugs to T cells. Whereas, in the third we will conduct a pilot prospective study to determine the value of CD38 expression in identifying patients with SLE prone to infections. The identification of the CD8+CD38+ T cell subset to be expanded in SLE patients and role of CD38 in limiting their cytotoxic activity along with the design of new mice represent novel concepts in the field of lupus. The search for approaches to restore their cytotoxic activity and the clinical study to define them as a biomarker for SLE patients prone to infections represent the translational value of this line of research.